Plant-derived secondary metabolites form the basis of important segments of the good, pharmaceuticals, pesticide and cosmetic industries. Interest in such metabolites will continue to grow as e.g. plant sources of new and useful drugs are discovered. Moreover, it is becoming increasingly known that fungi, bacteria, algae and animal cells are also sources of potentially useful metabolic products. The recovery of useful metabolites from natural sources is in many instances constrained, however, by the remote location of such sources, and even more by the enormous quantities of source material which may be required for the isolation of utilizable quantities of the desired products, which problems are of course reflected in the often very high prices of the latter.
The problems of recovery of useful secondary metabolites from natural sources may potentially be circumvented by cell culture. Whereas in plants, for example, production of the desired products is often confined to a few specialized cells and specific differentiated tissues, as well as to limited stages in the development of the cells, under suitable cell culture incubation conditions, on the other hand, it should be possible to obtain a higher yield in the production of the metabolites, and independently of the metabolic periodicity often found in nature. In practice, however, cultured plant cells tend to lose their competence for the production of the desired metabolites, for various reasons, and to the inventors' knowledge, the only such commercial process at the present time is the production of shikonin from Lithospermum erythrorhizon cells in a two-stage process. Attempts to overcome such problems by cloning, selecting and subculturing, or by manipulating the culture medium, have so far not met with notable success.
If, as seems to be agreed, culture productivity is predominantly a function of the cells' own control mechanism, it should be more useful to be able to induce the synthesis of enzymes which produce useful metabolites at the gene level. It is known that enzymes may be induced by fungal elicitors after infection of plants or cultured cells by pathogens to produce phytoalexins. Elicitors are agents which induce plants to synthesize the mRNA's and enzymes required for the synthesis of the induced products (phytoalexins); extracts of mycelium or cell walls from the pathogens may serve as effective elicitors, which analysis has shown to comprise oligo- or polysaccharides and low molecular weight compounds. However, many pathogenic organisms which are sources of elicitors are relatively difficult to cultivate on a large scale. The present invention is based upon the discovery of elicitors which do not depend on the cultivation of pathogens.
These elicitors have been found to promote and induce the formation of useful metabolites in biological cells. By the term "promote" in this context, it is intended to convey that the production of useful metabolites is enhanced. However, the production of such metabolites is also induced in cell cultures which are otherwise inactive in this request.
It is accordingly an object of the present invention to provide substances which promote or induce the formation of useful metabolites in biological cells from diverse groups of organisms.
A further object of the invention is the provision of a method for the promotion or induction of the formation of useful metabolites in biological cells.
Yet a further object of the invention is the provision of such a method which utilizes elicitors.
Another object of the invention is to provide such a method by which the desired cell metabolic products may be produced in economically viable yields.
Yet another object of the invention is to provide such a method in which the elicitors are preformed.
Still another object of the invention is to provide such a method in which the elicitors are formed in situ.
A further object of the invention relates to elicitors which are novel substances.
Yet other objects of the invention will appear from the description which follows.